The leukocyte common antigen-related protein tyrosine phosphatase receptor regulates regenerative neurite outgrowth in vivo

Abstract

Drosophila and leech models of nervous system development demonstrate that protein tyrosine phosphatase (PTP) receptors regulate developmental neurite outgrowth. Whether PTP receptors regulate neurite outgrowth in adult systems or in regenerative states remains unknown. The leukocyte common antigen-related (LAR) receptor is known to be present in rodent dorsal root ganglion (DRG) neurons; therefore, the well established model of postcrush sciatic nerve regeneration was used to test the hypothesis that LAR is required for neurite outgrowth in the adult mammalian nervous system. In uninjured sciatic nerves, no differences in nerve morphology and sensory function were detected between wild-type and LAR-deficient littermate transgenic mice. Sciatic nerve crush resulted in increased LAR protein expression in DRG neurons. In addition, nerve injury led to an increase in the proportion of LAR protein isoforms known to have increased binding affinity to neurite-promoting laminin-nidogen complexes. Two weeks after nerve crush, morphological analysis of distal nerve segments in LAR-deficient transgenic mice demonstrated significantly decreased densities of myelinated fibers, decreased axonal areas, and increased myelin/axon area ratios compared with littermate controls. Electron microscopy analysis revealed a significant twofold reduction in the density of regenerating unmyelinated fibers in LAR-/- nerves distal to the crush site. Sensory testing at the 2 week time point revealed a corresponding 3 mm lag in the proximal-to-distal progression of functioning sensory fibers along the distal nerve segment. These studies introduce PTP receptors as a major new gene family regulating regenerative neurite outgrowth in vivo in the adult mammalian system.